Long COVID—unravelling a complex condition
Authors: Carol L Hodgson, Tessa Broadley
Journal: The Lancet Respiratory Medicine (2023)

Long COVID is an overarching term that was originally coined by patients and is widely used to describe ongoing symptoms after the acute phase of COVID-19, including both short-term symptoms (4–12 weeks) and longer-term sequelae (beyond 12 weeks). The term post-COVID-19 condition, developed by WHO, describes the continuation or development of new symptoms 3 months after the initial SARS-CoV-2 infection.1WHOPost COVID-19 condition (long COVID).https://www.who.int/europe/news-room/fact-sheets/item/post-covid-19-conditionDate: 2022Date accessed: May 30, 2023Google Scholar The incidence of long COVID is estimated to be 10–30% for people who are not hospitalised in the acute phase,2Davis HE McCorkell L Vogel JM Topol EJ Long COVID: major findings, mechanisms and recommendations.Nat Rev Microbiol. 2023; 21: 133-146Crossref PubMed Scopus (870) Google Scholar 50–70% for hospitalised patients,3Ceban F Ling S Lui LMW et al.Fatigue and cognitive impairment in post-COVID-19 syndrome: a systematic review and meta-analysis.Brain Behav Immun. 2022; 101: 93-135Crossref PubMed Scopus (541) Google Scholar and 10–12% for vaccinated individuals after acute infection.4Al-Aly Z Bowe B Xie Y Long COVID after breakthrough SARS-CoV-2 infection.Nat Med. 2022; 28: 1461-1467Crossref PubMed Scopus (371) Google Scholar Conservatively, at least 65 million individuals globally were estimated to have long COVID in 2023,2Davis HE McCorkell L Vogel JM Topol EJ Long COVID: major findings, mechanisms and recommendations.Nat Rev Microbiol. 2023; 21: 133-146Crossref PubMed Scopus (870) Google Scholar with cases increasing daily. Long COVID is a complex, multisystem condition with the potential to have a substantial impact on individuals and society, including increased disability, increased health-care costs, and economic and productivity losses.5Yang C Tebbutt SJ Long COVID: the next public health crisis is already on its way.Lancet Reg Health Eur. 2023; 28100612 PubMed Google Scholar More than 200 symptoms have been identified that can impact functioning and activities of daily living, encompassing physical, psychological, and cognitive function.2Davis HE McCorkell L Vogel JM Topol EJ Long COVID: major findings, mechanisms and recommendations.Nat Rev Microbiol. 2023; 21: 133-146Crossref PubMed Scopus (870) Google Scholar The symptoms and sequelae of long COVID can persist for weeks or months, fluctuate over time, or manifest as new-onset chronic conditions. The condition has placed an enormous burden on health-care systems. Despite some international collaboration, progress in understanding long COVID has been hindered by heterogeneous study designs, follow-up durations, and measurement methods.6O'Mahoney LL Routen A Gillies C et al.The prevalence and long-term health effects of long COVID among hospitalised and non-hospitalised populations: a systematic review and meta-analysis.EClinicalMedicine. 2023; 55101762 Summary Full Text Full Text PDF PubMed Scopus (208) Google Scholar A global, collaborative, multidisciplinary research agenda will be essential to improve the diagnosis and treatment of long COVID. Potential mechanisms contributing to long COVID include pathophysiological changes related to the virus (eg, microclotting), immunological and inflammatory dysregulation resulting from the acute infection, viral persistence, and, in patients with severe disease, known sequelae of critical illness (post-intensive care syndrome).7Needham DM Davidson J Cohen H et al.Improving long-term outcomes after discharge from intensive care unit: report from a stakeholders' conference.Crit Care Med. 2012; 40: 502-509Crossref PubMed Scopus (1618) Google Scholar In a Lancet Respiratory Medicine Series on the post-acute sequelae of COVID-19,8Singh SJ Baldwin MM Daynes E et al.Respiratory sequelae of COVID-19: pulmonary and extrapulmonary origins, and approaches to clinical care and rehabilitation.Lancet Respir Med. 2023; (published online May 19.)https://doi.org/10.1016/S2213-2600(23)00159-5Summary Full Text Full Text PDF Scopus (16) Google Scholar, 9Parotto M Gyöngyösi M Howe K et al.Post-acute sequelae of COVID-19: understanding and addressing the burden of multisystem manifestations.Lancet Respir Med. 2023; (published online July 17.)https://doi.org/10.1016/S2213-2600(23)00239-4Summary Full Text Full Text PDF PubMed Scopus (21) Google Scholar, 10Pandharipande P Williams Roberson S Harrison FE Wilson JE Bastarache JA Ely EW Mitigating neurological, cognitive, and psychiatric sequelae of COVID-19-related critical illness.Lancet Respir Med. 2023; (published online July 17.)https://doi.org/10.1016/S2213-2600(23)00238-2Summary Full Text Full Text PDF PubMed Scopus (7) Google Scholar the diagnosis, treatment, and management of long COVID are discussed, with a focus on respiratory, neurocognitive, psychological, and systemic sequelae of severe acute COVID-19. Known risk factors for long COVID include severe acute disease, comorbidities (eg, diabetes and chronic heart failure), and life-saving therapies such as invasive mechanical ventilation. In the first Series paper, Sally J Singh and colleagues8Singh SJ Baldwin MM Daynes E et al.Respiratory sequelae of COVID-19: pulmonary and extrapulmonary origins, and approaches to clinical care and rehabilitation.Lancet Respir Med. 2023; (published online May 19.)https://doi.org/10.1016/S2213-2600(23)00159-5Summary Full Text Full Text PDF Scopus (16) Google Scholar present a compelling argument for further research to understand the mechanisms that underlie long-term respiratory symptoms after COVID-19, particularly for patients who required hospital admission and received invasive mechanical ventilation. These sequelae might be due to the underlying disease or to life-saving therapies delivered in intensive care units (ICUs), such as prolonged invasive mechanical ventilation, sedation, and immobilisation, which are known to contribute to long-term morbidity in survivors. Pathological changes might be caused by SARS-CoV-2 infection or by immune-mediated injury to alveolar cells. Specific pulmonary sequelae, such as pulmonary fibrosis and thromboembolic disease, need careful assessment and management because they could lead to increased dyspnoea and physical dysfunction. Current rehabilitation strategies have been adapted from chronic respiratory disease practices and pulmonary rehabilitation programmes; however, further research is needed to establish whether these strategies are effective for long-term respiratory symptoms after COVID-19. Frailty is well recognised as a risk factor for both COVID-19 severity and poor outcomes after critical illness.11Hodgson CL Higgins AM Bailey MJ et al.The impact of COVID-19 critical illness on new disability, functional outcomes and return to work at 6 months: a prospective cohort study.Crit Care. 2021; 25: 382Crossref PubMed Scopus (58) Google Scholar, 12Ma Y Hou L Yang X et al.The association between frailty and severe disease among COVID-19 patients aged over 60 years in China: a prospective cohort study.BMC Med. 2020; 18: 274Crossref PubMed Scopus (61) Google Scholar In some countries, frailty is routinely assessed at ICU admission to identify patients who might require additional support. In the third paper in the Series, Matteo Parotto and colleagues9Parotto M Gyöngyösi M Howe K et al.Post-acute sequelae of COVID-19: understanding and addressing the burden of multisystem manifestations.Lancet Respir Med. 2023; (published online July 17.)https://doi.org/10.1016/S2213-2600(23)00239-4Summary Full Text Full Text PDF PubMed Scopus (21) Google Scholar review research indicating that up to 30% of COVID-19 survivors are frail after hospitalisation for COVID-19. The authors describe the complex interaction between pre-existing comorbidities, frailty, socioeconomic factors, ICU support, and subsequent outcomes of long COVID for patients and caregivers. This interaction has important implications for models of health-care delivery, which include careful assessment of physical and psychological function after hospital discharge, and review of nutrition, medications, and social support. Coordinated, multidisciplinary care for people with long COVID at risk of frailty and further research for vulnerable people and groups are needed. Some of the most commonly reported symptoms of long COVID are neuropsychological symptoms, including fatigue, memory loss, dizziness, loss of taste or smell, depression, and anxiety, all of which can affect activities of daily living and productivity. These sequelae have also been reported after non-COVID-19-related critical illnesses, such as acute respiratory distress syndrome and sepsis, and in survivors of prolonged mechanical ventilation. However, in a large study from the USA, in the 12 months after infection, survivors of COVID-19 had about a 40% higher risk of developing cerebrovascular or neurodegenerative disorders (eg, ischaemic and haemorrhagic stroke, or Alzheimer's disease or Parkinson's-like disease) than did controls without SARS-CoV-2 infection.13Xu E Xie Y Al-Aly Z Long-term neurologic outcomes of COVID-19.Nat Med. 2022; 28: 2406-2415Crossref PubMed Scopus (187) Google Scholar In the second paper in the Series, Pratik Pandharipande and colleagues10Pandharipande P Williams Roberson S Harrison FE Wilson JE Bastarache JA Ely EW Mitigating neurological, cognitive, and psychiatric sequelae of COVID-19-related critical illness.Lancet Respir Med. 2023; (published online July 17.)https://doi.org/10.1016/S2213-2600(23)00238-2Summary Full Text Full Text PDF PubMed Scopus (7) Google Scholar provide a comprehensive review of the rationale for neuropsychological sequelae, associated risk factors, and potentially modifiable targets for treatment and prevention. The authors strongly advocate the use of evidence-based clinical practice guidelines for patients receiving mechanical ventilation,14Devlin JW Skrobik Y Gélinas C et al.Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU.Crit Care Med. 2018; 46: e825-e873Crossref PubMed Scopus (1857) Google Scholar such as limited use of neuromuscular blockade, avoidance of benzodiazepines, targeting of light sedation, regular awakening, spontaneous breathing trials, and rehabilitation. The identification and treatment of severe acute respiratory COVID-19 has improved survival outcomes, but the optimum approach to management of long COVID and its sequelae remains uncertain. In the Series, considerations for the follow-up and ongoing care of patients with long COVID are discussed by international experts. Key recommendations include further research to understand the pathophysiological mechanisms of multisystem sequelae of COVID-19; approaches to care in the acute phase that mitigate the symptoms of long COVID; use of predictive biomarkers to distinguish patients who are likely to benefit from established rehabilitation therapies; further investigation into effective strategies for reducing breathlessness, including group rehabilitation, rehabilitation via telemedicine, and individual breathing exercises; dedicated multidisciplinary clinics that can provide care and support for patients and also serve as a platform for research; and efforts to develop novel preventive and therapeutic treatments for long COVID. Clinicians, researchers, and other stakeholders need to advocate collaborative global research, with dedicated education and training for the health-care workforce and a public communication campaign to highlight ongoing challenges as a result of long COVID. Finally, patients with long COVID should be meaningfully engaged in the design and conduct of clinical trials to address key research questions aimed at improving the quality of their survival. We declare no competing interests. Respiratory sequelae of COVID-19: pulmonary and extrapulmonary origins, and approaches to clinical care and rehabilitationAlthough the exact prevalence of post-COVID-19 condition (also known as long COVID) is unknown, more than a third of patients with COVID-19 develop symptoms that persist for more than 3 months after SARS-CoV-2 infection. These sequelae are highly heterogeneous in nature and adversely affect multiple biological systems, although breathlessness is a frequently cited symptom. Specific pulmonary sequelae, including pulmonary fibrosis and thromboembolic disease, need careful assessment and might require particular investigations and treatments. Full-Text PDF Mitigating neurological, cognitive, and psychiatric sequelae of COVID-19-related critical illnessDespite advances in the treatment and mitigation of critical illness caused by infection with SARS-CoV-2, millions of survivors have a devastating, post-acute infection syndrome known as long COVID. A large proportion of patients with long COVID have nervous system dysfunction, which is also seen in the distinct but overlapping condition of post-intensive care syndrome (PICS), putting survivors of COVID-19-related critical illness at high risk of long-lasting morbidity affecting multiple organ systems and, as a result, engendering measurable deficits in quality of life and productivity. Full-Text PDF Post-acute sequelae of COVID-19: understanding and addressing the burden of multisystem manifestationsIndividuals with SARS-CoV-2 infection can develop symptoms that persist well beyond the acute phase of COVID-19 or emerge after the acute phase, lasting for weeks or months after the initial acute illness. The post-acute sequelae of COVID-19, which include physical, cognitive, and mental health impairments, are known collectively as long COVID or post-COVID-19 condition. The substantial burden of this multisystem condition is felt at individual, health-care system, and socioeconomic levels, on an unprecedented scale. Full-Text PDF